1. Field of the Invention
The present invention is generally directed to medical devices having short-term contact with the organism, as e.g. balloon catheters coated with at least one layer containing at least one antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, fungicidal and/or anti-thrombotic agent, methods for manufacturing these substance-releasing application aids and the use of these medical devices for the prevention of restenoses of the affected corporal lumina.
2. Description of the Relevant Art
Since the end of the 1980s metallic tubular stent grafts adjusted to the corporal lumen have been established ever the more for the prevention of restenosis, i.e. the prevention of re-occlusion of vessels, the graft pressing from the inside against the vascular wall. Further development of these grafts known as stents to a drug-coated “drug eluting stents” is intensively pursued at the time because of positive results in minimizing restenosis rates in comparison with uncoated stents.
These long-term implants substituted continuously PCTA (percutaneous transluminal coronary angioplasty) carried out since the 1960s and nowadays occupy the major part of interventions performed, since re-occlusion rates of uncoated stents are in several cases lower than occlusions recurring after PCTA performance.
Successfully realised in drug eluting stents, the idea of combining mechanical and chemical prophylaxis was already investigated since the early days of stents in balloon catheters for preventing restenosis of coronary arteries and used in different varieties in clinical studies.
The drug-loaded balloon catheter, however, could not prevail over the stent. The reasons are obvious:
In PCTA the occluded part is enlarged for a short time of 1 to 3 minutes by means of an inflatable balloon at the catheter tip, if necessary repeated for more than two times. Herein the vessels must be overstretched in such a way that the occlusion is removed. From this procedure microlesions result in the vascular wall reaching up to the adventitia. After removing the catheter the lesioned vessel is left alone so that considerably high performance is required for the healing process, in dependence of the inflicted lesion grade resulting from the duration, the repetitions and the grade of overstretching. This is reflected in the high re-occlusion rate after PCTA.
In stent implantation the balloon catheter is used as a transport and implant aid so that also herein overstretching of the vascular wall occurs, but in this case overstretching is only needed for the time of stent dilation. If the stent is unalterably stuck in the correct position the balloon is deflated again and can be removed. Thus the time of the once overstretch is reduced. The reduction in restenosis rate shows that this reduced overstretch time and the likewise reduced degree of overstretching in stents can lead already to a reduced rate in post-treatment, despite of introducing exogenous material into the body. This promising advance didn't leave much space for further optimizing PCTA since there was confidence that stents as permanent implants are hopeful carriers of a new preferably restenosis-free era which led to a preferential use down to the present day. PTCA is only performed in less severe cases and in particularly severe cases ahead of a stent implantation. The next goal in stent history is the 100% sure prevention of restenosis. Therefore the search for the combination of an ideal drug and an ideal preferably biodegradable stent has set out. Suppression of cellular reactions is mainly accomplished during the first days and weeks by means of preferably antiproliferative, immunosuppressive and/or antiphlogistic agents and their likewise active derivatives/analogues and metabolites. The active agents and/or combinations of active agents are used herein in a sensible way for wound healing or for its support.
The improvements balloon catheters have undergone recently were related up to now mainly to the ability of placing a stent precisely and safely. PCTA as an independent method was widely replaced.
But when using PCTA there are advantages over the stent, not least because thus at no time after performing the treatment an exogenous object is present in the organism as an additional stress factor or initiator of sequelae as is restenosis. Therefore there are up to now links to the studies on drug-releasing balloon catheters carried out in the late 1980s.
Thus different embodiments of balloon catheters were described for example, in which the outer surface being in direct contact with the environment has openings through which an active agent liquid or solved under pressure during dilation is pressed against the vascular wall (e.g. in U.S. Pat. No. 5,087,244, U.S. Pat. No. 4,994,033, U.S. Pat. No. 4,186,745).
For example, EP 0 383 429 A discloses a balloon catheter with tiny openings trough which a heparin solution is released to the vascular wall during dilation.
Several disadvantages as a lower uptake of the active agent into the vascular wall, missing control on dosage, problems with the balloon material etc. have kept the option of an exogenous object-free treatment of stenoses in suspense. Coating balloons analogous to stents with active agents with or without a polymeric matrix caused also problems, on the one hand in the short contact time and consequently a lower substance release from the catheter to its environment, and on the other hand in the considerable difficulties to bring the coating on the balloon unscathed to its destination, before and during dilation.
Only recently a substance releasing balloon catheter became an alternative to stents (CardioNews Letter, 04-21-2006). It involves a balloon catheter dipped into a solution of paclitaxel and a radiocontrast medium which led in a one year clinical study to a reduction in restenosis rate from 40 to 9%, in comparison to an uncoated balloon catheter. For example, such a balloon catheter is disclosed in WO 2004 28582 A1. Though these first results seem to be promising typical problems of such a treatment haven't been overcome.
In any case the optical resolution reached by the coating with a contrast medium is favourable, but the amount of the active agent effectively released and taken up at the site of action after PTCA performance remains individual and uncontrolled, since already after introducing the balloon catheter into the bloodstream starting from the groin to the heart an unquantifiable portion of the coating comes off. Additionally, also during balloon dilation further parts of the coating crumble away and are carried away from the surface by the bloodstream. Consequently, a part of the concentration of the active agent applied to the balloon catheter doesn't reach the affected site, but can be regarded simply as an ineffective intravenous administration. The amount of the lost portion can't be controlled and thus is not available for an optimal provision at the affected site. What is left on the balloon catheter must be sufficient for achieving a promising therapy, but the question remains how much substance actually reaches its target and is absorbed from the vascular wall.
Thus the alternative of a stent free restenosis treatment with this balloon catheter shall be brought on a new, effective and controllable road.
Furthermore, the conventional method of dip or spray coating for catheter balloons has the great disadvantage that it can never be determined how much substance actually was applied to the balloon surface which basically leads to a clear overdosage. Moreover it becomes ever the more important in regulatory affairs and for attaining marketing authorizations to provide well defined balloon coatings for which the substance amount was exactly determined. Conventional methods of dipping the balloon catheter several times in a coating solution or of exposing the balloon to a spray stream or mist of the coating solution didn't yield reproducible results, so that the application of a defined substance amount was not possible.